Radiation therapy is the treatment of diseases and conditions, especially the treatment of tumors, including malignant tumors, with radiation. In radiation therapy, the ultimate aim is to destroy the malignant tissue without causing excessive radiation damage to nearby healthy, and possibly vital, tissue. This is difficult to accomplish because of the proximity of malignant tissue to healthy tissue.
Medical personnel and investigators have developed methods for preferentially irradiating deep seated diseased tissue as opposed to healthy tissue. These methods include the use of high energy X-ray beams together with cross fire and rotational techniques which create a radiation pattern that is maximized at the site of the diseased tissue. Nonetheless, some absorption and damage inevitably occurs to healthy tissue in the path through which radiation passes to arrive at deep-seated diseased tissue.
One method of limiting the zone of irradiation utilizes radioactive articles in the form of small, radioactive “seeds,” which are permanently or temporarily implanted at the zone to be irradiated. Such seeds contain a radioactive source disposed within a sealed capsule. The small size of the therapeutic seeds allows the seeds to be inserted or implanted within or near the tissue to be treated, for example, to totally surround the treated tissue.
Radiation treatment can involve a temporary implantation of a radioactive source for a calculated period, followed by its removal. Alternatively, the radioactive source can be implanted in the patient permanently and left to decay to an inert state over a predictable time. The use of temporary or permanent implantation depends on the disease or condition being treated, the radioisotope selected, and the duration and intensity of required treatment.
The advantages of interstitial implantation of a radiation-emitting article for localized tumor treatment have long been recognized. Interstitially implanted articles concentrate the radiation at a zone where radiation treatment is needed, e.g. near or within diseased tissue in order to directly affect diseased tissue, while exposing normal, healthy tissue to substantially less radiation than beaming radiation into the body from an external source.
Implanting radioactive articles in proximity to or directly within diseased or damaged tissue within a body is a therapy referred to as brachytherapy (i.e. short-range therapy). Brachytherapy is a general term for a medical treatment involving placement of a radioactive source near diseased tissue. Brachytherapy has been proposed for use in the treatment of a variety of diseases and conditions, including arthritis and cancer, for example, breast, brain, liver, and ovarian cancer, and especially prostate cancer in men [see for example, J. C. Blasko et al., The Urological Clinics of North America, 23, 633-650 (1996), and H. Ragde et al., Cancer, 80, 442-453 (1977)]. This form of therapy permits the application of larger doses of radiation directly to diseased or damaged tissue, like tumors.
Permanent implants for prostate cancer treatment comprise radioisotopes with relatively short half-lives and lower energies relative to radioisotopes used in temporary implants. Examples of permanently implantable radioisotopes include iodine-125 and palladium-103. The radioisotope generally is disposed on a substrate, which is encapsulated in a metal casing, for example, a titanium casing, to form a “seed,” which is then implanted in the patient.
Radioactive seeds are disclosed, for example, in Lawrence U.S. Pat. No. 3,351,049 and Kubiatowicz U.S. Pat. No. 4,323,055. U.S. Pat. No. 3,351,049 discloses conventional brachytherapy seeds comprising titanium containers encapsulating ion exchange resin beads onto which a radioactive ion, e.g. 125I or 103Pd has been adsorbed. U.S. Pat. No. 3,351,049 also discloses that 103Pd, preferably carrier-free, could be plated on a 3.5 mm long plastic rod. However, U.S. Pat. No. 3,351,049 does not disclose any method of plating carrier-free 103Pd onto the plastic rod. As discussed hereafter, the uniform distribution of carrier-free 103Pd on a substrate has been an ongoing and unsolved problem. U.S. Pat. No. 4,323,055 discloses brachytherapy seeds comprising a coating of radioactive silver iodide on a silver wire encapsulated inside a titanium container. WO 97/19706 discloses the immobilization of a radioactive powder within a polymeric matrix.
The seeds disclosed in prior patents comprise a tiny sealed capsule having an elongate cavity containing the radioisotope, e.g., iodine-125 (125I) or palladium-103 (103Pd), adsorbed onto a substrate. Such seeds are suitable for use with radioisotopes that emit radiation capable of penetrating the capsule walls. Therefore, the seeds generally contain radioisotopes that emit γ-radiation or low-energy X-rays, as opposed to β-emitting radioisotopes. Because of the low energy X-rays emitted by 125I and 103Pd, and the short half-life of 125I and 103Pd, the seeds can remain implanted in the tissue of a patient indefinitely without excessive damage to surrounding healthy tissue or excessive exposure to other individuals near the patient.
In order to function effectively, radiation emitting from the radioisotope within the seed should not be blocked or otherwise unduly attenuated. Seeds based on metal wire substrates have the disadvantage that a portion of the radioactivity is absorbed by the wire substrate itself, i.e. the radioactive emissions from the seed are attenuated by the wire. The amount of radioactivity absorbed by the wire increases as the atomic number (i.e. Z) of the metal wire substrate increases. The precise amount of attenuation is related to the identity and the dimensions of the wire substrate. For example, silver iodide-125 coated on an 0.5 mm diameter silver wire has up to about 40-50% of the radioactivity absorbed by the silver wire. Therefore, in the manufacture of a radioactive seed of a preselected activity, additional 125I is loaded onto the wire to account for the absorption of radioactivity by the wire and also by the seed capsule. As the preselected radioactivity of the seed increases, the cost of the extra amount of radioisotope which is loaded onto the wire substrate also increases.
Radiation emitted from the radioisotope also should be distributed uniformly from the seed in all directions, i.e. an isotropic radial distribution. Providing a uniform distribution of radiation from a seed has been difficult to accomplish. For example, present-day seeds have a radioisotope adsorbed onto a carrier substrate, which is placed into a metal casing that is welded at the ends. The most advantageous materials of construction for the casing which encapsulates the radioisotope-laden carrier are stainless steel, titanium, and other low atomic number metals, with titanium and titanium alloys being preferred. However, problems exist with respect to sealing casings made from these materials.
In particular, metallic casings typically are sealed by welding, but welding of such small casings is difficult because welding can locally increase the casing wall thickness, or can introduce higher atomic number materials at the ends of the casing where the welds are located. The presence of such localized anomalies can significantly alter the geometrical configuration at the welded ends, resulting in undesirable shadow effects in the radiation pattern emanating from the seed. Such seeds also have the disadvantage of providing a non-homogeneous radiation dose to the target due to their construction, i.e. the relatively thick ends attenuate the emanating radiation more than the relatively thin body of the seed.
Problems also have been encountered in homogeneously applying the radioisotope to the substrate. Brachytherapy seeds are small in size, and the amount of radioisotope present in each seed is extremely small, e.g. less than 1×10−6 g of radioactive isotope per seed. The amount of radioisotope present in each seed necessarily decreases as the specific activity of the isotope increases. This presents severe handling and manufacturing problems with respect to homogeneously applying a small chemical amount of radioisotope onto the substrate, especially when the radioisotope is carrier-free. These problems, together with safety problems, increase in scope as the radioactivity of the isotope increases.
Several patents are directed to implantable radioactive seeds for use in brachytherapy. Examples of such patents include Kubiatowicz U.S. Pat. No. 4,323,055; Suthanthiran U.S. Pat. No. 4,891,165; Russell, Jr. et al. U.S. Pat. Nos. 4,784,116 and 4,702,228; Lawrence U.S. Pat. No. 3,351,049; Good U.S. Pat. No. 5,342,283; Carden, Jr. U.S. Pat. No. 5,405,309; and Langton et al. U.S. Pat. No. 5,460,592.
U.S. Pat. No. 5,405,309 addresses the previously mentioned problem of uniformly distributing carrier-free 103Pd on a substrate. The specific problem addressed by U.S. Pat. No. 5,405,309 is that carrier-free radioisotopes are present in a seed at vanishingly small amounts, and that use of an extremely dilute carrier-free radioisotope solution presents significant handling problems, in addition to safety problems associated with an intensely radioactive composition. U.S. Pat. No. 5,405,309 teaches that 103Pd can be applied more easily, evenly, and safely to a substrate by admixing non-radioactive palladium metal (i.e. carrier Pd) with carrier-free 103Pd to increase the physical mass of the palladium and facilitate application of the palladium onto the substrate.
Because 103Pd is expensive to produce, it is important that application of the 103Pd radioisotope onto the substrate is as efficient and reproducible as possible. The method of U.S. Pat. No. 5,405,309 utilizes electroplating, i.e. a process involving passage of an electric current, to achieve a homogeneous distribution of 103Pd on the substrate. However, the addition of non-radioactive palladium metal, i.e. carrier Pd, to facilitate electroplating of 103Pd attenuates the low energy X-ray emissions of the 103Pd adsorbed onto the substrate by providing an additional high Z material that attenuates radiation emanating from radioactive 103Pd. The result is that additional 103Pd must be applied to the substrate to attain at least a threshold radioactive dose. This adds to the cost of such 103Pd seeds. It is a major disadvantage to prepare costly carrier-free 103Pd (eg. using a high energy cyclotron), then to use a process that provides a product wherein a portion of the radioactive emissions are effectively lost by dilution of carrier-free 103Pd with carrier Pd.
Although the above patents illustrate improvements in seeds for use in brachytherapy, the art still suffers from the problem of providing a 103Pd seed that, simultaneously, is easy to manufacture and has a uniform distribution of radioisotope on the substrate, while minimizing attenuation of radioactivity emanating from the seed. The present invention is directed to providing 103Pd brachytherapy seeds having these attributes.